Cystic Fibrosis (“CF”) is the most common autosomal recessive disorder in Europe and the USA, impacting one in every 2500 children born in Western Countries. It is a disease caused by mutations of the CF transmembrane conductance regulator protein (“CFTR”). While this genetic mutation leads to several respiratory, reproductive and gastrointestinal complications, the primary cause of morbidity and mortality in these subjects results from the destructive effects of chronic pulmonary colonization with Pseudomonas aeruginosa (“P. aeruginosa”). Medical records indicate approximately 80% of subjects with CF will host P. aeruginosa by the age of 25. See Cystic Fibrosis Foundation Subject Registry: Annual Data Report (2010). In addition to the increased susceptibility to P. aeruginosa, CF lungs are characterized by chronic inflammation and progressive fibrosis. At present, the molecular mechanisms that mediate the hallmarks of CF disease, i.e., infection susceptibility, inflammation, and fibrosis, require definition.
P. aeruginosa infection of epithelial cells is initiated by contact of the pathogen with the cell surface. Several binding molecules for P. aeruginosa have been identified, including CFTR, Fibronectin, α5β1-integrin and glycolipids including asialo-GM1. See Pier et. al., “Role Of Mutant CFTR In Hypersusceptibility Of Cystic Fibrosis Subjects To Lung Infections,” Science. 271, 64-67 (1996); Schroeder et. al., “CFTR Is A Pattern Recognition Molecule That Extracts Pseudomonas aeruginosa LPS From The Outer Membrane Into Epithelial Cells And Activates NF-kappa B Translocation,” Proc. Natl. Acad. Sci. U.S.A. 99, pp. 6907-6912 (2002); deBentzmann et. al., “Asialo GM1 Is A Receptor For Pseudomonas aeruginosa Adherence To Regenerating Respiratory Epithelial Cells,” Infect. Immun. 64(5) pp. 1582-1588 (1996); deBentzmann et. al., “Pseudomonas aeruginosa Adherence To Remodeling Respiratory Epithelium,” Eur. Respir. J. 9 pp. 2145-2150 (1996); Roger et. al., “Fibronectin And α5β1-integrin Mediate Binding Of Pseudomonas aeruginosa To Repairing Airway Epithelium,” Eur. Respir. J. 13 pp. 1301-1309 (1999); Saiman et. al., “Pseudomonas aeruginosa Pili Bind To AsialoGM1 Which Is Increased On The Surface Of Cystic Fibrosis Epithelial Cells,” J. Clin. Invest. 92 pp. 1875-1880 (1993); and Davies et. al., “Reduction In The Adherence Of Pseudomonas aeruginosa To Native Cystic Fibrosis Epithelium With Anti-AsialoGM1 Antibody And Neuraminidase Inhibition,” Eur. Respir. J; 13 pp. 565-570 (1999).
Therefore, identification of epithelial receptors for P. aeruginosa that are specifically altered in CF and involved in the high infection susceptibility of these subjects to P. aeruginosa, is an important consideration in the development of new strategies for CF—and concomitant pathogenic infection—prophylaxis and treatment. Such molecules would be ideal targets to prevent the initial contact of the pathogen with bronchial epithelial cells in CF subjects and, thus, to prevent the infection very early.
Current methods of treating and preventing disease pathogenesis in subjects afflicted with a disease or condition raise toxicity and efficacy concerns.
The present invention is directed to overcoming these deficiencies in the art by, for example, by correcting the abnormal expression of primary binding molecules of bacterial pathogens to bronchial epithelial cells in vivo through a unique membrane lipid mediated mechanism.